Neurodegenerative diseases or disorders are caused by the progressive damage or death of neurons. Neurons are nerve cells in the brain whose primary function is to assist in the memory process. The damage or death of neurons leads to a gradual deterioration of the functions controlled by the affected part of the nervous system.
Neurodegenerative diseases or disorders often occur as a result of oxidative stress. Oxidative stress occurs to the cells in an organism when the effects of pro-oxidants (such as free radicals, reactive oxygen and reactive nitrogen species) exceed the ability of anti-oxidants to neutralise them. When levels of free radicals or other pro-oxidants increase to such an extent, they can cause damage to cell membranes which in turn may result in cell death or damage to genetic material.
The group of neurodegenerative diseases or disorders are characterised by changes in the normal neuronal function, leading, in most cases, to neuronal death. Most of these diseases are associated, especially in late stages, with severe neuronal loss.
With an increasingly ageing population more and more people are affected by neurodegenerative diseases or disorders. According to the National Institute of Neurological Disorders and Stroke, there are more than 600 different neurodegenerative diseases or disorders.
Some of the most common types of neurodegenerative diseases or disorders include Alzheimer's disease, Parkinson's disease and Multiple sclerosis.
The process of degeneration of the neurons in an organism is often as a result of glutamate excitotoxicity. Glutamate is a signalling chemical and under normal conditions the concentration of glutamate tends to be quite low. Glutamate is required at these low concentrations for crucial brain functions such as memory and learning. When glutamate concentrations increase, the process of neurodegeneration begins.
When the brain is deprived of oxygen either due to a neurodegenerative disease, such as Alzheimer's disease, or a neurodegenerative disorder such as an ischemic event (such as a stroke), or due to trauma (such as a closed head injury), an abnormal build-up of glutamate occurs.
Neurodegeneration takes place when the glutamate attaches to receptor proteins on a cells surface. These N-methyl-D-aspartate (NMDA) receptors then open an excess of calcium channels causing the intracellular concentration of calcium to increase rapidly. Calcium ions activate phospholipase A (PLA), which in turn results in the release of arachidonic acid and superoxide radicals.
Neurodegeneration proceeds from the destructive effects of oxidative radicals caused by the glutamate flood. The radicals cause disruption of essential reactions in the neurones and this leads to degeneration or death of the cell.
Some neuroprotective agents have been studied in clinical trials in stroke patients. One drug Dextrorphan is of limited use however due to its side effects of hallucinations, agitation and hypotension.
Another drug, Selfotel, unfortunately showed trends towards a higher mortality rate with patients treated with the drug rather than placebo, and as such the trials were halted. The drug Cerestat also had its trials terminated because of concerns with the benefit-to-risk ratio of the drug.
Clearly there is a significant requirement for an efficacious treatment to prevent or treat neurodegenerative diseases or disorders.
Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells. Phytocannabinoids are the cannabinoids derived from cannabis plants. Endocannabinoids are endogenous cannabinoids found in humans and other animals. The phytocannabinoids can be isolated from plants or produced synthetically. When isolating the phytocannabinoids from plants they can be purified to the extent that all of the other naturally occurring compounds, such as, other minor cannabinoids and plant molecules such as terpenes are removed. This purification results in a purity of greater than 99% (w/w) of the target cannabinoid.
It was discovered that glutamate toxicity could be prevented to some extent by pure/synthetic preparations of the cannabinoids tetrahydrocannabinol (THC) or cannabidiol (CBD), (Hampson et al. 1998). The cannabinoids were tested in vitro on neuronal cultures exposed to glutamate. Although further research from an in vivo study by the same group failed to find a difference between animals treated with pure CBD and the placebo treated animals (Rosenthal et al. 2000).
The cannabinoid cannabidiol (CBD) is known to exhibit neuroprotective, anti-inflammatory and anti-oxidant properties and as such has been tested in models of neuro-toxicity and neurodegeneration. Promising results have been achieved with CBD in the control of toxicity induced by β-amyloid peptide, which is responsible for the neurodegeneration in Alzheimer's patients (luvone et al. 2009).
The beneficial effects of CBD in the treatment of neurodegenerative diseases in an in vivo model of Alzheimer's disease have also been demonstrated (Esposito et al. 2007).
The application GB2479153 demonstrates the anti-epileptic effects of the phytocannabinoid CBDV.
The application GB2450493 discusses the CB1 and CB2 cannabinoid receptor antagonist properties of the phytocannabinoid CBG.
The International application WO 2008/024490 discusses the potential for cannabinoid agonists to be used to treat opioid abuse.
The patent application GB2377633 discusses formulations which comprise THC and CBD and may also comprise CBDV.
In the granted United Kingdom patent, GB2432312, the applicants demonstrated that the administration of cannabinoids, as extracts from cannabis plants, were more efficacious than that of the purified compounds, in the prevention of neural degeneration. In particular cannabinoid-rich extracts comprising as a predominant cannabinoid either tetrahydrocannabinol (THC) or cannabidiol (CBD) were particularly efficacious in the prevention of neurodegeneration. The applicants additionally found that a combination of the two cannabinoid extracts were particularly effective neuroprotectants.
At least 85 different cannabinoids have been isolated from the cannabis plant and their structures differ depending on where cyclisation of the precursor cannabinoid cannabigerol (CBG) occurs. It is well known that the different cannabinoids demonstrate different properties. For example the cannabinoid tetrahydrocannabinol (THC) is a known agonist of the CB1 receptor; however the propyl variant of this cannabinoid, tetrahydrocannabivarin, (THCV), has been shown to act in an opposite manner at the CB1 receptor and is classed as a CB1 antagonist. It should therefore be appreciated that although the class of cannabinoids are all found to be produced in various strains of the cannabis plant it cannot be assumed that they all share the same properties.
The cannabinoid cannabidiol (CBD), unlike THC and THCV shows little activity at the CB1 or CB2 receptors.
In the present application, the applicants have discovered that further cannabinoids which are molecularly distinct from CBD, THC and THCV are able to prevent or treat neurodegenerative diseases or disorders. These cannabinoids are: cannabichromene (CBC), and cannabidivarin (CBDV). The model of neurodegenerative disease exemplified by the applicants is Alzheimer's disease.
Alzheimer's disease is the most prevalent neurodegenerative disease affecting elderly people. In 2006 there were 26.6 million sufferers of the disease worldwide and it is predicted that by 2050 Alzheimer's disease will affect 1 person in 85 globally. The cause and progression of the disease are not well understood and the currently used treatments only offer a small symptomatic benefit. There are currently no treatments which are able to delay or halt the progression of the disease. More than 500 clinical trials have been conducted for identification of a possible treatment for Alzheimer's disease yet there still remains a lack of suitable treatment options.